COMMON BRAND NAMES

HOW SUPPLIED

DOSAGE & INDICATIONS

For the treatment of acute influenza A virus infection or influenza B virus infection.

Oral dosage

Adults

75 mg PO twice daily for 5 days. The CDC suggests that longer treatment courses for patients who remain severely ill after 5 days of treatment can be considered.

Children weighing more than 40 kg and Adolescents

75 mg PO twice daily for 5 days. The CDC suggests that longer treatment courses for patients who remain severely ill after 5 days of treatment can be considered.

Children weighing 24 kg to 40 kg

60 mg PO twice daily for 5 days ; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

Children weighing 16 kg to 23 kg

45 mg PO twice daily for 5 days ; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

Children weighing 15 kg or less

30 mg PO twice daily for 5 days ; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

Infants

3 mg/kg/dose PO twice daily for 5 days ; extended courses may be considered for patients who remain severely ill after 5 days of treatment. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure.

Term Neonates 14 to 29 days

3 mg/kg/dose PO twice daily for 5 days ; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

3 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

Premature Neonates 38 to 40 weeks postmenstrual age†

1.5 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

Premature Neonates younger than 38 weeks postmenstrual age†

1 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

For seasonal influenza prophylaxis.

Oral dosage

Adults

75 mg PO once daily for at least 10 days after close contact and for up to 6 weeks during a community outbreak. Safety and efficacy have been demonstrated for up to 6 weeks in immunocompetent patients and safety has been demonstrated for up to 12 weeks in immunocompromised patients (efficacy has not been demonstrated). The duration of protection lasts for as long as dosing is continued. High risk patients may require prophylaxis during the entire influenza season. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known identified case. Oseltamivir treatment for 42 days has been efficacious in preventing influenza in 92% of those in residential nursing home settings during a flu outbreak; note that 80% of the residents had previously received influenza vaccination.

Children weighing more than 40 kg and Adolescents

75 mg PO once daily for at least 10 days after close contact and for up to 6 weeks during a community outbreak. Safety and efficacy have been demonstrated for up to 6 weeks in immunocompetent patients and safety has been demonstrated for up to 12 weeks in immunocompromised patients (efficacy has not been demonstrated). The duration of protection lasts for as long as dosing is continued. High risk patients may require prophylaxis during the entire influenza season. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known identified case. Oseltamivir treatment for 42 days has been efficacious in preventing influenza in 92% of those in residential nursing home settings during a flu outbreak; note that 80% of the residents had previously received influenza vaccination.

Children weighing 24 kg to 40 kg

60 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The Centers for Disease Control (CDC) recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.

Children weighing 16 kg to 23 kg

45 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The Centers for Disease Control (CDC) recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.

Children weighing 15 kg or less

30 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The Centers for Disease Control (CDC) recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.

Infants 3 months and older†

3 mg/kg/dose PO once daily. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO once daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. The duration of therapy is dependent on type of exposure: 7 days after the last known exposure; 2 weeks for those vaccinated during an outbreak; a minimum of 2 weeks and up to 1 week after the last identified case for control of outbreaks in long-term care facilities and hospitals. High-risk patients may require prophylaxis during the entire influenza season.

Infants 1 to 2 months†

Because of the lack of data in this age group, chemoprophylaxis is not recommended unless the exposure situation is judged to be critical. A variety of oseltamivir dosages have been safely used for influenza prophylaxis in infants in limited studies. A dosage of 1 mg/kg/dose PO twice daily for 10 days was effective in a small study of 13 neonates (mean gestational age 39 weeks [range, 36 to 41 weeks]) exposed to influenza H1N1; no patients developed influenza.

Neonates†

Because of the lack of data in this age group, chemoprophylaxis is not recommended unless the exposure situation is judged to be critical. A variety of oseltamivir dosages have been safely used for influenza prophylaxis in neonates in limited studies. A dosage of 1 mg/kg/dose PO twice daily for 10 days was effective in a small study of 13 neonates (mean gestational age 39 weeks [range, 36 to 41 weeks]) exposed to influenza H1N1; no patients developed influenza.

For the treatment of novel influenza A viruses associated with severe human disease†, including avian influenza A virus infection†.

3 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

Premature Neonates greater than 40 weeks postmenstrual age and Term Neonates

For prophylaxis of novel influenza A viruses associated with severe human disease†, including avian influenza prophylaxis†.

Oral dosage

Adults

75 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Children weighing 40 kg or more and Adolescents

75 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Children weighing 24 kg to 40 kg

60 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Children weighing 16 kg to 23 kg

45 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Children weighing 15 kg or less

30 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Term Neonates and Infants 14 days and older

3 mg/kg/dose PO twice daily. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Premature Neonates greater than 40 weeks postmenstrual age and Term Neonates 0 to 13 days

3 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Premature Neonates 38 to 40 weeks postmenstrual age

1.5 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

Premature Neonates younger than 38 weeks postmenstrual age

1 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

†Indicates off-label use

MAXIMUM DOSAGE

Adults

75 mg PO twice daily for 5 days for treatment; 75 mg/day for up to 6 weeks for prophylaxis. 300 mg/day PO for 10 days has been used for avian influenza A (H5N1) treatment.

Geriatric

75 mg PO twice daily for 5 days for treatment; 75 mg/day for up to 6 weeks for prophylaxis.

Adolescents

75 mg PO twice daily for 5 days for treatment; 75 mg/day for up to 6 weeks for prophylaxis.

Children

Weight more than 40 kg: 75 mg PO twice daily for 5 days for treatment; 75 mg/day PO for up to 6 weeks for prophylaxis.Weight 24 to 40 kg: 60 mg PO twice daily for 5 days for treatment; 60 mg/day PO for up to 6 weeks for prophylaxis.Weight 16 to 23 kg: 45 mg PO twice daily for 5 days for treatment; 45 mg/day PO for up to 6 weeks for prophylaxis.Weight 15 kg or less: 30 mg PO twice daily for 5 days for treatment; 30 mg/day PO for up to 6 weeks for prophylaxis.

Infants

9 to 11 months: 3 mg/kg/dose PO twice daily for 5 days is the FDA-approved dosage for treatment; however, 3.5 mg/kg/dose PO twice daily has been used off-label; not indicated for prophylaxis; however, 3.5 mg/kg/dose PO once daily for 10 days has been used off-label.3 to 8 months: 3 mg/kg/dose PO twice daily for 5 days for treatment; not indicated for prophylaxis; however, 3 mg/kg/dose PO once daily for 10 days has been used off-label.1 to 2 months: 3 mg/kg/dose PO twice daily for 5 days for treatment; not indicated for prophylaxis.

Neonates

Term Neonates 14 days and older: 3 mg/kg/dose PO twice daily for 5 days for treatment; not indicated for prophylaxis.Premature Neonates older than 40 weeks postmenstrual age and Term Neonates 0 to 13 days: Safety and efficacy have not been established; however, 3 mg/kg/dose PO twice daily for 5 days has been used off-label for treatment; not indicated for prophylaxis.Premature Neonates 38 to 40 weeks postmenstrual age: Safety and efficacy have not been established; however, 1.5 mg/kg/dose PO twice daily for 5 days has been used off-label for treatment; not indicated for prophylaxis.Premature Neonates younger than 38 weeks postmenstrual age: Safety and efficacy have not been established; however, 1 mg/kg/dose PO twice daily for 5 days has been used off-label for treatment; not indicated for prophylaxis.

DOSING CONSIDERATIONS

Hepatic Impairment

No dosage adjustments are recommended for patients with mild to moderate hepatic impairment (Child-Pugh score <= 9). The safety and pharmacokinetics of oseltamivir in patients with severe hepatic impairment have not been established.

Renal Impairment

The following dose adjustments are recommended for adult patients with renal impairment. Dose adjustment recommendations are unavailable for pediatric patients; however, similar dose adjustments should be considered, particularly in pediatric patients receiving the adult dosage.

Intermittent hemodialysis (ESRD patients with CrCl <= 10 ml/min)For influenza treatment: 30 mg after every hemodialysis cycle; treatment duration not to exceed 5 days. The initial dose may be given immediately, with subsequent doses administered after each dialysis.For influenza prophylaxis: 30 mg after alternate hemodialysis cycles. The initial dose may be given prior to the start of dialysis.

ADMINISTRATION

May be taken orally with or without food; tolerability may be enhanced if taken with food.Begin treatment within 2 days of the onset of symptoms. Begin prophylaxis within 2 days of exposure.

Oral Solid Formulations

For patients who cannot swallow capsules, the commercially available oral suspension is the preferred formulation. However, if the oral suspension is not available, the capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar dissolved in water. If the appropriate strengths of capsules are not available to mix with sweetened liquids and the commercially available oral suspension is not available, then a compounded supply of oral suspension can be prepared by the pharmacist (see below).

Oral Liquid Formulations

Oral suspension (commercially available 6 mg/ml concentration): Shake well prior to use. Provide the appropriate oral syringe to the patient or caregiver. NOTE: The manufacturer supplies a bottle adapter and a 10 ml oral dispensing syringe with each bottle. For patients >= 41 kg (>= 89 pounds), two administrations with the 10 ml syringe are required to achieve the full dose (10 ml followed by another 2.5 ml).

Reconstitution of commercially available 6 mg/ml oral suspension:Review the reconstitution instructions for the particular product and package size, as the amount of water required for reconstitution varies from manufacturer to manufacturer.Loosen powder from sides of the bottle. Add the specified amount of water and shake well for 15 seconds. The final oseltamivir concentration is 6 mg/ml.Remove the child-resistant cap and push bottle adapter into the neck of the bottle.Close tightly with the child-resistant cap. This will ensure proper sealing of the bottle.Storage after reconstitution: Use within 17 days of reconstitution when stored under refrigeration or within 10 days if stored at room temperature. Write the expiration date on the label.

Extemporaneous Compounding-Oral

Extemporaneous 6 mg/ml oral suspension (using capsules):NOTE: This compounded suspension is for use only during emergency situations and should not be used for convenience or when the FDA-approved oral suspension is commercially available.NOTE: The recommended vehicles are Cherry Syrup (Humco), Ora-Sweet SF (sugar-free), or simple syrup; other vehicles have not been studied. The final oseltamivir concentration in the compounded suspension is 6 mg/ml, which is the SAME as the commercially available oral suspension.NOTE: The total volume of suspension needed to prepare a full course (5-day treatment course or 10-day course of prophylaxis) is based on the patient's dose (see below). If the oseltamivir dose is between the doses listed, the total volume of the oral suspension should default to the next greater dose listed. See Dosage section for specific weight- and age-based dosage recommendations.Oseltamivir dose of <= 15 mg: Prepare a 37.5 ml suspension using three (3) 75-mg capsules (225 mg oseltamivir), 2.5 ml of water, and 34.5 mg of recommended vehicle.Oseltamivir dose of 30 mg: Prepare a 75 ml suspension using six (6) 75-mg capsules (450 mg oseltamivir), 5 ml of water, and 69 ml of recommended vehicle.Oseltamivir dose of 45 mg: Prepare a 100 ml suspension using eight (8) 75-mg capsules (600 mg oseltamivir), 7 ml of water, and 91 ml of recommended vehicle.Oseltamivir dose of 60 mg: Prepare a 125 ml suspension using ten (10) 75-mg capsules (750 mg oseltamivir), 8 ml of water, and 115 ml of recommended vehicle.Oseltamivir dose of 75 mg: Prepare a 150 ml suspension using twelve (12) 75-mg capsules (900 mg oseltamivir), 10 ml of water, and 137 ml of recommended vehicle.

Compounding the 6 mg/ml oral suspension:Add the above specified volume of water to a polyethyleneterephthalate (PET) or glass bottle; a funnel may be used to prevent spillage.Carefully open each capsule and transfer contents into the PET or glass bottle.Gently swirl the suspension for at least 2 minutes.Slowly add the above specified volume of vehicle to the bottle; a funnel may be used to prevent spillage.Shake well for 30 seconds to completely dissolve the active drug and to ensure homogenous distribution of the dissolved drug in the resulting suspension. It should be noted that oseltamivir phosphate readily dissolves in the recommended vehicles and that the suspension is due to some of the inert ingredients of the capsules that are insoluble in these vehicles.Place an ancillary label on the bottle stating 'Shake Well Before Use'.The compounded oral suspension is stable for 5 days when stored at room temperature 25 degrees C (77 degrees F) or for 5 weeks (35 days) under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). However, if pharmacies are preparing batches of the extemporaneously compounded suspension due to high prescription volume, the compounded suspension must be refrigerated until dispensed, stirred thoroughly before dispensing, and refrigerated by the patient at home.Dispense with a graduated oral syringe for measuring small amounts of suspension.

STORAGE

CONTRAINDICATIONS / PRECAUTIONS

General Information

Oseltamivir is contraindicated in any patient who is hypersensitive to the drug or to any component of the formulation.

Infection, viral infection

Serious bacterial infections may begin with influenza-type symptoms or may coexist with or occur as complications during a course of influenza. There is no evidence of oseltamivir efficacy to treat viral infection or other types of infection caused by agents other than influenza virus A and B. Data on the treatment of influenza B infection are limited; only 3% of patients in the clinical trials were infected with this virus. There are no data available to support the efficacy of oseltamivir therapy in patients who begin treatment 48 hours after the onset of symptoms.

Immunosuppression, vaccination

The use of oseltamivir should not affect the evaluation of individuals for annual influenza vaccination in accordance with the guidelines for the US Centers for Disease Control (CDC). In addition, oseltamivir does not interfere with the antibody response to the inactivated influenza vaccine. There is concern, however, about possible interference with the viral replication necessary after administration of the live attenuated influenza vaccine for the proper development of immunity. Do not administer the live attenuated influenza vaccine within 48 hours after oseltamivir administration, and wait at least 2 weeks after administration of the live attenuated vaccine to begin oseltamivir therapy, unless earlier oseltamivir therapy is medically necessary. According to the manufacturer, efficacy of oseltamivir has not been established in immunocompromised patients or those with immunosuppression. However, the Centers for Disease Control and Prevention (CDC) recommends oseltamivir for the treatment and prevention of influenza in patients with immune deficiencies and those receiving immunosuppressive medications.

Efficacy of oseltamivir, as measured by time to alleviation of all symptoms, has not been established in patients with chronic pulmonary disease or cardiac disease. However, oseltamivir studies have included 'at-risk' adult patients with cardiac disease, adults with chronic obstructive pulmonary disease (COPD) (i.e., chronic bronchitis or emphysema), and older pediatric patients with asthma; the incidence of complications in these patient populations did not differ between oseltamivir and placebo. In addition, studies evaluating safety and efficacy of the drug in elderly (age older than 65 years) and younger adult patients have found no overall difference. Safety and efficacy of oseltamivir have been established in elderly nursing home residents who took oseltamivir for up to 42 days for the prevention of influenza. Many of these individuals had cardiac or respiratory disease, and most had received the influenza vaccine that season. Patients with chronic health conditions are at higher risk for developing complications associated with influenza infection, and the Centers for Disease Control and Prevention (CDC) recommends oseltamivir use in these patient populations for the treatment and prophylaxis of influenza. No information is available regarding oseltamivir treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered as having an imminent risk of hospitalization.

Renal failure, renal impairment

Oseltamivir is not recommended for patients with end stage renal failure (creatinine clearance 10 mL/min or less) who are not receiving dialysis. Dosage adjustments are recommended in adult patients with moderate to severe renal impairment (creatinine clearance 60 mL/min or less) and for patients on dialysis; consider similar adjustments in pediatric patients. The active metabolite of oseltamivir is greater than 99% renally eliminated; therefore, patients with renal impairment are at increased risk for drug accumulation and adverse effects.

Hepatic disease

The safety and pharmacokinetics of oseltamivir have not been established in patients with severe hepatic disease. During clinical studies, the pharmacokinetics of oseltamivir were not changed in patients with mild or moderate hepatic impairment.

Psychosis

Neuropsychiatric adverse reactions of self-injury and delirium (psychosis) have been reported during postmarketing use of oseltamivir; some cases resulted in fatal outcomes. These reactions were primarily reported in pediatric patients and often occurred abruptly and resolved rapidly. Since influenza infection itself is associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior), the role of oseltamivir in causing these reactions is unclear. Patients with influenza who are receiving oseltamivir should be closely monitored for signs of abnormal behavior. The risks and benefits of continuing oseltamivir should be evaluated if neuropsychiatric events occur.

Children, infants, neonates, Reye's syndrome

Neuropsychiatric adverse reactions of self-injury and delirium have been reported post-marketing (mostly in Japan) with oseltamivir. These reactions were primarily reported in children; monitor patients for signs of abnormal behavior. Dosing in children is typically weight-based; the drug requires dosage adjustment for children < 13 years of age weighing < 40 kg. In clinical trials, pediatric patients >= 1 year of age who were treated with oseltamivir within 2 days of symptom onset experienced a reduction in the duration of flu of about 1.5 days. Based on these trials and trials in adults, oseltamivir was approved for treatment of influenza in children, infants, and neonates >= 14 days of age. The drug is also effective in preventing the spread of influenza in close contacts in children at least 1 year of age. However, prophylactic use of oseltamivir beyond 10 days duration has not been evaluated in children 1—12 years old. Safety and efficacy of oseltamivir prophylaxis have not been established in infants and neonates; however, the CDC has issued recommendations for infants as well as treatment recommendations for neonates and premature neonates (see Dosage).. According to the manufacturer, animal studies have identified high blood and brain concentrations of oseltamivir and associated deaths in very young animals; immature blood-brain barriers might be susceptible to increased oseltamivir penetration and adverse events may result. A single dose of 1000 mg/kg oseltamivir phosphate (about 250 times the recommended human pediatric dose) in 7-day-old rats resulted in deaths associated with unusually high exposure to both oseltamivir and oseltamivir phosphate; concentrations in the brain were roughly 1500 times those seen in adult rats that received the same dose. No adverse effects were noted after 7 to 21 day old rats received doses of 500 mg/kg/day. The clinical significance of these preclinical data to human infants is uncertain. It is generally recommended that the drug not be administered to infants prior to the maturation of the blood-brain-barrier (i.e. approximately 1 year of age). Aspirin has been associated with the occurrence of Reye's syndrome when given to children with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with varicella, influenza, or other viral infection.

Hereditary fructose intolerance

Patients with hereditary fructose intolerance should be warned that oseltamivir powder for oral suspension contains 11 g of sorbitol per 13-g bottle. This results in a 75 mg dose of the suspension delivering 2 g of sorbitol, which is above the daily maximum limit of sorbitol. Dyspepsia and diarrhea may occur in patients with hereditary fructose intolerance.

Pregnancy

Oseltamivir is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women; however, a collection of observational studies have evaluated drug exposure in approximately 1500 pregnant women. Although, individually, these studies lacked adequate sample size, pooled data found no increased risk of congenital malformations when compared to the general population. In addition, the gestational period in which exposure occurred appeared to have no effect on pregnancy outcome, as approximately 400 women were exposed during the first trimester. In animal studies, slight and marked maternal toxicities and a dose-dependent increase in skeletal abnormalities in offspring were observed. The CDC states that the benefits of treatment against the influenza virus likely outweigh the theoretical risks of antiviral use. Additionally, pregnant women are known to be at higher risk for complications from infection and severe disease among women have been reported in past pandemics. The manufacturer states that oseltamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

According to the manufacturer, limited data suggest oseltamivir and oseltamivir carboxylate are excreted in human breast milk. The concentration of oseltamivir and oseltamivir carboxylate in breast milk was found to be lower than the concentrations in plasma following a single 75 mg oral dose. The estimated infant exposure to oseltamivir, assuming a 2.75 kg infant receiving 750 ml of breast milk daily, was 0.76 mcg/kg/day. This dose is much lower than oseltamivir doses used in neonates and infants for treatment of influenza; thus, exposure through breast milk is unlikely to cause fetal toxicity. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

DRUG INTERACTIONS

Probenecid: (Minor) Coadministration of oseltamivir and probenecid results in a two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dosage adjustments are required when oseltamivir is given concomitantly with probenecid.

PREGNANCY AND LACTATION

Pregnancy

Oseltamivir is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women; however, a collection of observational studies have evaluated drug exposure in approximately 1500 pregnant women. Although, individually, these studies lacked adequate sample size, pooled data found no increased risk of congenital malformations when compared to the general population. In addition, the gestational period in which exposure occurred appeared to have no effect on pregnancy outcome, as approximately 400 women were exposed during the first trimester. In animal studies, slight and marked maternal toxicities and a dose-dependent increase in skeletal abnormalities in offspring were observed. The CDC states that the benefits of treatment against the influenza virus likely outweigh the theoretical risks of antiviral use. Additionally, pregnant women are known to be at higher risk for complications from infection and severe disease among women have been reported in past pandemics. The manufacturer states that oseltamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

According to the manufacturer, limited data suggest oseltamivir and oseltamivir carboxylate are excreted in human breast milk. The concentration of oseltamivir and oseltamivir carboxylate in breast milk was found to be lower than the concentrations in plasma following a single 75 mg oral dose. The estimated infant exposure to oseltamivir, assuming a 2.75 kg infant receiving 750 ml of breast milk daily, was 0.76 mcg/kg/day. This dose is much lower than oseltamivir doses used in neonates and infants for treatment of influenza; thus, exposure through breast milk is unlikely to cause fetal toxicity. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

MECHANISM OF ACTION

Oseltamivir is activated to oseltamivir carboxylate, which acts as a neuraminidase (sialidase) inhibitor. Oseltamivir carboxylate selectively inhibits the neuraminidases of influenza A and B and does not significantly inhibit human lysosomal neuraminidase. Influenza virus neuraminidase is a surface glycoprotein that catalyzes the cleavage of the linkage between a terminal sialic acid and adjacent sugar residue. This action promotes the spread of virus in the respiratory tract by several mechanisms. Viral neuraminidase promotes the release of virions from infected cells; promotes the penetration of virus into respiratory epithelial cells; prevents the formation of viral aggregates; prevents viral inactivation by respiratory mucus; induces cellular apoptosis by activating transforming growth factor beta; and induces cytokines including interleukin-1 and tumor necrosis factor. Oseltamivir carboxylate acts extracellularly and binds to an unoccupied area of influenza neuraminidase that results in competitive inhibition of the enzyme.

In vitro studies show that oseltamivir carboxylate and zanamivir have a similar EC50 (50% effective inhibitory concentration) to influenza virus A and B. It would appear that mechanisms of resistance would be similar for the 2 agents; cross-resistance has been observed in vitro. Genetic analysis shows that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. The prevalence of oseltamivir-resistant viruses varies based on season and geographic location. Selection of influenza A viruses resistant to oseltamivir appear to occur at higher frequencies in children. During small pediatric studies, the incidence of oseltamivir treatment-associated resistance for influenza A/H1N1 and influenza A/H3N2 were 27% to 37% and 3% to 18%, respectively. The actual risk of resistance to oseltamivir during clinical use cannot be determined from these small pediatric studies.

Influenza viruses are classified into 3 distinct types, influenza A, influenza B, and influenza C. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. Influenza infection may be attributed to either influenza A virus or influenza B virus. Influenza A virus subtypes include H1N1 and H3N2. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.

PHARMACOKINETICS

Oseltamivir is administered orally. Oseltamivir is extensively converted to oseltamivir carboxylate by hepatic esterases; oseltamivir carboxylate is the active form of the drug. The binding of oseltamivir carboxylate to plasma proteins is low (3%).

Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. Oseltamivir has an elimination half-life of 1 to 3 hours, and > 90% of oseltamivir is eliminated by conversion to oseltamivir carboxylate. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. The elimination half-life of oseltamivir carboxylate is 6 to 10 hours. Oseltamivir carboxylate is more than 99% eliminated by renal excretion. The renal clearance of oseltamivir carboxylate exceeds the glomerular filtration rate, which suggests tubular secretion in addition to glomerular filtration.

Affected cytochrome P450 isoenzymes: none

Oral Route

Following oral administration, 75% of the dose reaches the systemic circulation as oseltamivir carboxylate; < 5% of the total dose reaches the systemic circulation as oseltamivir. Administration with food has no effect on the Cmax or AUC values for oseltamivir carboxylate.

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